Atherosclerosis (or arteriosclerosis) is the term used to describe progressive narrowing and hardening of the arteries that can result in an aneurysm, thrombosis, ischemia, embolism formation or other vascular insufficiency. The disease process can occur in any systemic artery in the human body. For example, atherosclerosis in the arteries that supply the brain (e.g., the carotids, intracerebral, etc.,) can result in stroke. Gangrene may occur when the peripheral arteries are blocked, and coronary artery disease occurs when the arteries that supply oxygen and nutrients to the myocardium are affected. The atherosclerosis process involves lipid-induced biological changes in the arterial walls resulting in a disruption of homeostatic mechanisms that keep the fluid phase of the blood compartment separate from the vessel wall. The atheromatous plaque consists of a mixture of inflammatory and immune cells, fibrous tissue, and fatty material such as low density lipoproteins (LDL). Also, the incidence of atherosclerosis is continuing to increase as a result of the Western diet and the growing proportion of elderly in the population. Additionally, since atherosclerosis is the primary cause of myocardial infarction, cerebral infarction, cerebral apoplexy and so forth, there is a need for its effective prevention and better treatment.
On a given day, the average American consumes about 450 mg of cholesterol and produces an additional 500 to 1,000 mg in the liver and other tissues. Another source of cholesterol is the 500 to 1,000 mg of biliary cholesterol that is secreted into the intestine daily; about 50 percent is reabsorbed. It is well known that the levels of plasma cholesterol have been positively correlated with the incidence of clinical events associated with coronary heart disease as well as atherosclerosis which is characterized by plaque formation. The plaque inhibits blood flow, promotes clot formation and can ultimately cause heart attacks, stroke and claudication.
Elevated serum cholesterol levels (>200 mg/dL) have been indicated as a major risk factor for heart disease, the leading cause of death among Americans. As a result, experts have recommended that those individuals at high risk decrease serum cholesterol levels through dietary changes, a program of physical exercise, and lifestyle changes. It is recommended that the intake of saturated fat and dietary cholesterol be strictly limited and that soluble fiber consumption be increased. Strictly limiting the intake of saturated fat and cholesterol does not, itself, present a risk to proper health and nutrition. Even where saturated fat and cholesterol are severely restricted from the diet, the liver remains able to synthesize sufficient quantities of cholesterol to perform necessary bodily functions.
The regulation of whole-body cholesterol homeostasis in humans and animals involves modulation of cholesterol biosynthesis, bile acid biosynthesis, and the catabolism of the cholesterol-containing plasma lipoproteins. The liver is the main organ responsible for cholesterol biosynthesis and catabolism and, for this reason, it is a prime determinant of plasma cholesterol levels. The liver is the site of synthesis and secretion of very low density lipoproteins (VLDL) which are subsequently metabolized to low density lipoproteins (LDL) in the circulation. LDL are the predominant cholesterol-carrying lipoproteins in the plasma and an increase in their concentration is correlated with increased atherosclerosis.
More recently, experts have begun to examine the individual components of the lipid profile, in addition to the total cholesterol level. While an elevated total cholesterol level is a risk factor, the levels of the various forms of cholesterol which make up total cholesterol may also be risk factors. Elevated low-density lipoprotein (LDL) is a cause for concern, as these loosely packed lipoproteins are more likely to lodge within the cardiovascular system leading to the formation of plaque. Low levels of high-density lipoproteins (HDL) are an additional risk factor, as they serve to sweep artery clogging cholesterol from the blood stream. A better indication of risk appears to be the ratio of total cholesteron:HDL.
Another important factor in determining cholesterol homeostasis is the absorption of cholesterol in the small intestine. On a daily basis, the average human consuming a Western diet eats 300 to 500 mg of cholesterol. In addition, 600 to 1000 mg of cholesterol can traverse the intestines each day. This latter cholesterol is a component of bile and is secreted from the liver. The process of cholesterol absorption is complex and multifaceted. The literature on cholesterol illustrates that approximately 50% of the total cholesterol within the intestinal lumen is absorbed by the cells lining the intestines (i.e., enterocytes). This cholesterol includes both diet-derived and bile- or hepatic-derived cholesterol. Much of the newly-absorbed cholesterol in the enterocytes is esterified by the enzyme acyl-CoA:cholesterol acyltransferase (ACAT). Subsequently, these cholesteryl esters are packaged along with triglycerides and other components (i.e., phospholipids, apoproteins) into another lipoprotein class, chylomicrons.
Chylomicrons are secreted by intestinal cells into the lymph where they can then be transported to the blood. Virtually all of the cholesterol absorbed in the intestines is delivered to the liver by this route. When cholesterol absorption in the intestines is reduced, by whatever means, less cholesterol is delivered to the liver. The consequence of this action is a decreased hepatic lipoprotein (VLDL) production and an increase in the hepatic clearance of plasma cholesterol, mostly as LDL. Thus, the net effect of an inhibition of intestinal cholesterol absorption is a decrease in plasma cholesterol levels.
Several cholesterol-lowering agents were discovered during the 1950s and 1960s. However, most of them had undesirable side effects. The search for a cleaner drug to treat hypercholesterolemia started in he early 1970s. Various experiments on animals and humans had shown that cholesterol could either be absorbed from the diet, or if the diet was lacking sufficient cholesterol to meet the body's needs, then it could be synthesized—mainly in the liver (82%) and the intestine (11%). However, if the diet was rich in cholesterol then synthesis within the body virtually stopped. Previous work had shown that cholesterol production within the body was controlled by a feedback mechanism in which cholesterol inhibited the enzyme 3-hydroxy-3-methylglutaryl-CoA reductase (HMG Co-A reductase). By inhibiting this enzyme, the conversion of HMG-CoA to mevalonic acid was stopped—this step being the key to the body in creating cholesterol. Accordingly, the inhibition of cholesterol biosynthesis by 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA) inhibitors (such as the statins family of compounds i.e., mevastatin, lovastatin, pravastatin, fluvastatin, simvastatin, rosuvastatin, cerivastatin and atorvastatin) has been shown to be an effective way to reduce plasma cholesterol and reduce atherosclerosis.
The production of mevalonic acid (a precursor to cholesterol) is brought about when HMG Co-A binds to the enzyme HMG Co-A reductase. After this has occurred, NADPH binds to the enzyme/substrate combination. A reaction then occurs in which NADPH is oxidized to NADP-CoA, and HMG Co-A is reduced to mevalonic acid. As the affinity of HMG Co-A reductase is substantially higher for the statins than it is for HMG Co-A, the statins act as a reversible competitive inhibitor to the enzyme reaction and less mevalonic acid is produced in its presence. Thus the cholesterol production pathway is broken. The introduction of a competitive inhibitor for HMG Co-A reductase results in two physiological responses. In compensation for the inhibition, cells begin to produce more HMG Co-A. The direct reduction in circulating cholesterol is therefore only small. However, the number of low-density lipoprotein (LDL) receptors on hepatocytes increases markedly. As the liver is responsible for removing LDL's (of which cholesterol is a component) from plasma via the LDL receptor mechanism, blood cholesterol levels also fall dramatically.
Plant derived long-chained aliphatic alcohols have also been documented to reduce serum cholesterol levels in experimental models, healthy humans and in type II hypercholesterolemic patients. These aliphatic alcohols, collectively known as policosanol, have been employed in the treatment of elevated serum cholesterol levels in only the past five years, but policosanol has shown much promise, as reported in a number of published human clinical trials. The mechanism of action has not yet been elucidated, but policosanol's effectiveness is attributed to its influence on the bio-synthesis of cholesterol within the liver. This accounts for the ability of policosanol not only to decrease total cholesterol, but also to decrease LDL serum levels and increase HDL levels.
Development of therapeutic agents for the treatment of atherosclerosis and other diseases associated with cholesterol metabolism has been focused on achieving a more complete understanding of the biochemical pathways involved.
Combination therapies of lipid lowering agents have been described previously as having a synergistic hypolipidemic effect. Nevertheless, in practice, many combinations of existing lipid regulating agents are contraindicated, limiting the options of prescribing physicians for patients requiring greater reductions of plasma LDL-cholesterol levels and greater elevations in HDL cholesterol levels. Thus, although there are a variety of hypercholesterolemia therapies, there is a continuing need and a continuing search in this field of art for alternative therapies.
The present invention addresses a long felt need for new medications to further reduce the risk of atherosclerotic disease. This is especially true for patient populations at a higher risk than the population at large, e.g. patients suffering from hypercholesterolemia and hyperlipoproteinemia. The long felt need is addressed by use of combination therapy for reducing cholesterol levels by using a combination of HMG-CoA reductase inhinbitors and compounds that inhibit cholesterol synthesis at a point between the formation of acetate and mevalonate. The prior art is silent regarding combinations of HMG-CoA reductase inhinbitors with policosanol and their use for lowering cholesterol.